This invention relates to a method and pharmaceutical composition for treating herpes group virus infections in mammals, with specific emphasis upon the treatment of herpes simplex virus infections in humans.
There are four separate herpes group viruses which infect and cause disease in humans. These are (1) herpes simplex virus 1 and 2. (HSV-1 and HSV-2); (2) cytomegalovirus (CMV); (3) varicella-zoster virus (VZ) and Epstein-Barr virus (EB). The distinct clinical entities caused by herpes simplex virus (types 1 and 2) are given in Table 1. The clinical entities caused by cytomegalovirus, varicella-zoster virus, and Epstein-Barr virus are described below.
TABLE 1 ______________________________________ DISEASE ATTRIBUTABLE TO HERPES SIMPLEX VIRUS INFECTION ______________________________________ Herpes Labialis Disseminated Herpes Genital Herpes Occupational Herpes Neonatal Herpes Herpetic Gingivostomatitis Herpetic Keratitis Meningitis (Aseptic) Eczema Herpeticum Encephalitis ______________________________________
Herpes viruses are a large family of viruses which contain deoxyribonucleic acid (DNA) and are surrounded by an envelope. They occur throughout nature and have been found to infect many forms of life including vertebrates and invertebrates and even fungi. One of their primary biological characteristics is to latently exist in an infected host after the primary or initial infection and in some instances, cause recurrent disease in that host due to exacerbation of the virus from the latent state. This state of latency can endure over the lifetime of an individual animal.
The first infection in humans caused by HSV-1 is generally an infection in childhood in which the virus actively infects the mucous membranes of the mouth and oral region. The clinical entity produced by this infection is called gingivostomatitis. After the initial infection runs its course, the virus becomes latent in the nerve centers (ganglia) which supply the sensory nerves to the infected area. At any point in the life of the individual, after the initial infection, due to various trigger factors which have commonly been called "stress factors," and with an unknown mechanism, the virus may reappear and cause infection in different parts of the oral or facial skin region and the resultant clinical entity is called "herpes labialis." The common names for this malady are "cold sores" or "fever blisters."
A second significant and serious disease, most often caused by HSV-2, is genital herpes (herpes progenitalis) which occurs most often as a direct result of venereal acquisition of HSV-2 from an infected individual. Once HSV-2 initially infects the genital region, it too becomes latent in the individual and can reoccur, giving rise to a series of herpes genital lesion episodes. As seen in Table 1, there are other clinical entities caused by HSV-1 and HSV-2 and these are all important in human disease.
Varicella-zoster (VZ) virus is another virus of the herpes group which causes distinct and well-known diseases in man. The first disease caused by VZ virus is chicken-pox (varicella). Generally, chicken-pox is a childhood disease, the virus being acquired through respiratory droplets spread from an infected individual to an uninfected individual. Chicken-pox is a systemic disease which produces vesicular lesions over the body of the infected person. Once the disease runs its course, the virus becomes latent in the nerves of the body and remains in a latent state throughout the life of the individual.
In some individuals, for unknown reasons, the virus may reoccur later in life and cause the clinical entity known as shingles (zoster). Shingles can be a particularly painful disease, and the pain can endure even after the lesions of the disease have cleared up (post-zoster neuralgia).
Cytomegaloviruses (CMV) are a group of viruses within the herpes virus family which are widespread in humans and numerous other mammals. A great majority of human CMV infections are subclinical; that is, the primary infection occurs with no signs or symptoms. An exception to this is a congenital infection which occasionally gives rise to cytomegalic inclusion body disease of infants. There is also a mononucleosis-like syndrome caused by this virus.
A great majority of serious cases due to CMV infection come from recurring infections in immunocompromised individuals, such as in transplant patients and in cancer patients. It has been estimated that silent CMV infections have occurred in a majority of humans by the time adulthood is reached.
Epstein-Barr (EB) virus is the causative agent of infectious monomucleosis and is another member of the herpes virus family. This virus is unique among the herpes virus group in its ability to replicate only in certain types of lymphoid cells called B-cell lymphocytes. Infections mononucleosis is a self-limited lymphoproliferative disease which generally has a benign course and only rarely is severe. There is, occasionally, deep organ involvement, such as in the liver and other potentially serious complications of this disease. To date, there is no known effective treatment for EB virus infection.
Some drugs are available for treatment of herpes group virus infections of humans. However, they do not and cannot be used to treat all herpes diseases.
In general, antiviral drugs fall into discreet categories based upon their mechanism of action. There are nucleotide analogs which interfere or halt RNA or DNA synthesis. Some compounds have the property of inhibiting maturation steps in the replication cycle of viruses. Others interfere with binding or absorption of viruses to specific hosts cells or tissues. Still others prevent the uncoating of the viruses following absorption into a cell and some restrict the spread of progeny viruses from cell to cell or from infected tissues to other sites.
The currently available anti-herpetic agents fall into the nucleic acid inhibition category and generally are purine or pyrimidine analogs. The first of these is IUDR (which is 5'-iodo 2' deoxyuridine). This compound is a halogenated pyrimidine analog and is taken up into cells, phosphorylated by viral and cellular thymidine kinases, and is incorporated into DNA instead of thymidine. DNA is replicated, but viral maturation fails because defective proteins are specified by the altered DNA. This compound is toxic to both uninfected and infected cells and as such, is less selective than the following agents. IUDR is used clinically only for herpetic keratitis lesions (eye infections) because rapid re-epithelialization of the cornea somewhat mitigates its toxicity.
The second agent somewhat useful for treating herpes infections is Ara-C (1-beta arabinofuranosylcytosine). Ara-C is an analog of cytidine and is taken up by infected and uninfected cells and is incorporated into nascent DNA following phosphorylation by viral and cell phosphorylases. It is less inhibitory to DNA synthesis than is IUDR, but it inhibits both DNA polymerase and the nucleotide diphosphate reductases. It is toxic to both infected and uninfected cells and is not used clinically because of this toxicity.
Yet another anti-herpetic compound is Ara-A (9-beta arabinofuranoxyladenine). Ara-A is deaminated to arabinosyl hypoxanthine and is phosphorylated to mono-, di-, and triphosphate derivatives which act as competitive inhibitors of DNA polymerase. The DNA polymerase that is specified by the herpes simplex virus is inhibited to a greater extent than cellular DNA polymerase and Ara-A is therefore more selective than IUDR or Ara-C. Ara-A is utilized clinically for the treatment of herpetic encephalitis.
Acyclovir (9-2-beta hydroxyethomethylguanine) is another anti-herpetic drug, a guanine analog which is converted to the active triphosphate by herpes specified thymidine kinases in infected cells. It is more readily phosphorylated in infected than in uninfected cells. The phosphorylated acylguanine inhibits viral DNA polymerase to a significantly greater degree than it does a cellular enzyme and is less toxic because of this. Acyclovir also seems to be less subject to metabolic degradation than other inhibitors. It is used clinically for primary genital herpes simplex infections and for disseminated herpes infections in immunocompromised individuals.
Phosphonoacetic acid specifically inhibits viral DNA polymerase but it is too toxic for use in humans. Trisodium phosphoformic acid inhibits herpes specified DNA polymerase and is less toxic than phosphonoacetic acid, but it is also mutagenic and is not used clinically. Interferon, extracted from human fibroblast lymphocytes or manufactured using recombinant DNA techniques is moderately effective in some reports of its use clinically but scientific studies have demonstrated that it fails to inhibit viral replication directly. Its mechanism of action is attributable to protection of uninfected cells adjacent to infected cells by an unknown protective action. Interferons are cell specific, not viral specific, in their effects and cause antiviral resistance by activating cellular genes for antiviral proteins which interact with cell surface. RNA and slow replicating viruses are the best interferon inducers and responders. Herpes simplex is a poor interferon inducer and a poor responder to interferon treatment.
A whole array of other drugs, generally nucleotide inhibitors and anti-metabolites, have been shown to be effective in their antiviral properties in cell culture and sometimes in animals; however, these drugs have not been proved to be efficacious in the treatment of HSV infections in humans. Because of their cytotoxicity, many of these drugs likely will have highly toxic properties when used to treat humans for herpes infections.